functional group conversion : nucleophilic
DESCRIPTION
Functional Group Conversion : nucleophilic. Ref. "Comprehensive Organic Transformations" by Lorock, 1999. 1) Alcohol Activation. a. Sulfonation. + Pry.H Cl. pyridine. Generates non-nucleophilic byproducts. via. b. Halides. ** Through activation of alcohols **. i) from sulfonate. - PowerPoint PPT PresentationTRANSCRIPT
Functional Group Conversion : nucleophilic
Ref. "Comprehensive Organic Transformations" by Lorock, 1999
1) Alcohol Activation
a. Sulfonation
R OH + Cl S R'
O
O
O S R'
O
O
R
O S R'
O
O
2
or
Generates non-nucleophilic byproducts
pyridine+ Pry.HCl
R OH + Cl S Me
O
O
O S Me
O
O
R
Et3N
CH2Cl2
S CH2
O
O
via
b. Halides
R OH + R ClSOCl2
R OH + R BrPBr33 3
RO
SCl
OCl-
+
SO2
+
Cl-
P(OR)3+HBr
PH(OR)2+
O
R BrPH(OR)+
O
R BrHBr
OH
HBr
PH(OH)+
O
OH
** Through activation of alcohols **
i) from sulfonate
R OSO2R' + R XM X
ii) from other halides ---- Finkelstein Reaction
+ R X'M X'R X + M X
LiBrNaILiCl
AcetoneDMFDMSONMPAlcohol
excess Equilibrium control
NaCl
ppt formation helps !
addition of water needed
iii) Through activating agents
+ Ph3P XX YPh3P
Ph3P O + HX
R
Nu-
R Nu
Y-
ROH
Y-
+ PO(Ph)3
1. ROH + PPh3 + Br2 RBr
2. ROH + PPh3 + CCl4 RCl
+
Cl3C CCl3
O
or
3. Mitsunobu Reaction : Synthesis, 1 (’81)
ROH + PPh3 + DEAD + Nu- RNu
RO
PPh3
N N
EtOOC
COOEt
NNH
COOEt
COOEt
Nu-
+
POPh3
+
EtOOCNHNHCOOEt
Activates PPh3
HO
PPh3, DEAD
MeI
I
3. Mitsunobu Reaction : inversion of stereochemistry
4. Others
O
N
Et
Cl + R OH
O
N
Et
O + R Cl
O
N
Et
O
Cl-
R
PPh3, DEAD
ArCOOHOHO OArCOO
2) reactions of activated alcohols
a. one carbon homologation
+R X-CN R CN
b. Nitrogen nucleophiles
NaCN DMSO, 100oC
LiCN THF
+R X R NH
R' NH2
R'+ R N
R'
R
+ R NR'
R
R
Gabriel synthesis
+R X N
O
O
K N
O
O
R R NH2
hydrazine+
NHNH
O
O
Possible impurities
+R OH
LiN3
N F N OR N O+R N3
ROH + PPh3 + DEAD + DPPA RN3
Ph
OHO
(PhO)2P N3
DBU Ph
N3
+R X-N3 R N3
NaN3 DMF
NaN3 THF w/ R4PBr Phase transfer catalyst
NH2
NN
-N3
CH2Cl2
c. sulfur nucleophile : cf. Selenium, Phosphorous
+R X-SR' R S
R'
+ Me-I
NS N
SMe
Reactivity of the Electrophiles
benzyl > allyl > methyl > primary > secondary
sulphonates > iodidie > bromide > chloride
Phase transfer catalyst can enhance the reactivity when any of the reagents are not quite soluble
3) Nucleophilc reactions of ethers & esters -- deprotection methods
R O
CH3
R
O
OCH3
-Nu+
R OH
R
O
OH
Lewis acid
R OHRO
R'
L.A.
RO
R'
L.A.
Nu:+ R' Nu
BF3
BBr3
MgBr2
TMS-I
R’’SH
R COOHO
R'L.A.
L.A.
Nu:+ R' Nu
R
O
OR'
R
O
a. Classics
4) Esters & Amide formation
RCOOH + R'OH acid RCOOR'
b. through activation of alcohols
ROH + PPh3 + DEAD + R'COO- ROOCR'
RCOOH +Cl3C O
R'
NH
RCOOR' TL, 39, 1557(1998)
-- Mitsunobu reaction
-- Imidate intermediate
cf.ROH +
Cl3C OR'
NH
ROR'
c. unusual way
d. activation of caboxylic acids
RCOOH + CH2N2 RCOOCH3
* acid halides : RCOOH + SOCl2 RCOCl
+ (COCl)2 +DMF(cat.)
RCOOH + PPh3 + BrCCl3 RCOBr
RCOOH + CDI RCO-Im
Reaction: RCOCl + R'OH + DMAP (cat.) RCOOR'
RCOCl + R'NH2 RCONHR'
or
TMSCHN2
d. activation of caboxylic acids
•in situ activation to esters & amides DCC coupling
RCOOH + DCC + R'OH + DMAP RCOOR'
RCOOH + DCC + R'NH2 (+ HOBT) RCONHR'
R OH
O
+ N C N
NH
CN
O
O
R
DMAP
N
O
R
N
HOBT
O
O
RN
N
N
to ester
to amide
prevent ketene formation
racemization
NC
N NCl
EDCWater soluble DCC
d. activation of caboxylic acids
Alternatives to DCC
N Cl N O O
O
N N S
O
Cl
N S NS
+ PPh3
N
NS S
NN
+ PPh3
O
PN3
(PhO)2N
P
O
NO
OCl
O
O
BOP-Cl
DPC (Kim’s reagent)
e. From ester to amide
RCOOR' + R2Al-NHR'' RCONHR''
Homework
Chapter 3 : 1, 3, 5, 6, 13, 17
Due :
R OR'
O
+ R1 NH
R2 Me3Al
R N
O
R2
R1
Pyrophoric!!